Friday, March 14, 2025
3/14/2025
PROJECT SUMMARY/ABSTRACT Hemophilia is an x-linked bleeding disorder characterized by deficiencies in clotting factor VIII or IX. Patients suffer from frequent joint bleeding, which may lead to debilitating hemophilic arthropathy (HA). Both symptomatic and silent bleeds, as well as unnoticed microhemorrhages, generate hemosiderin deposits, the primary etiology of joint degeneration in HA. Non-invasive imaging of both hemosiderin and the subsequent damage it causes to cartilage and subchondral bone is important for optimizing costly prophylactic treatment plans and monitoring disease progression. While magnetic resonance imaging (MRI) is the gold standard for evaluation of HA, it has significant limitations including imprecise, only semi-quantitative evaluation of hemosiderin deposition, and an inability to detect both early iron deposition and degeneration in cartilage and subchondral bone. Ultrashort echo time (UTE) MRI sequences, with TEs ~100 times shorter than those of clinical sequences, can overcome these limitations. Using targeted UTE sequences, fast transverse relaxation signals from hemosiderin and the osteochondral junction (OCJ) can be directly detected with high contrast. This study aims to develop a complete package of UTE MRI techniques for evaluation of HA, including 1) accurate quantification of hemosiderin through volumetric mapping of T1, T2*, and susceptibility; 2) assessment of early cartilage damage by monitoring proteoglycan and collagen; and 3) evaluation of the OCJ, and aims to apply this package in cross-sectional and longitudinal studies of three groups of HA patients (mild, moderate, and severe), as well as an age-matched control group. In Aim 1 we will further optimize the speed, contrast, resolution, and accuracy of a series of 3D UTE MRI techniques for morphological and quantitative evaluation of hemosiderin in synovium, and for assessment of articular cartilage health and OCJ changes using a clinical 3T MR scanner. In Aim 2 we will evaluate the optimized 3D UTE and clinical MRI sequences for assessment of hemosiderin, cartilage, and the OCJ in ex vivo tissues from hemophilia patients following total knee arthroplasty (n=10) and from normal cadaveric human knee joints (n=10). We will compare UTE-based morphological and quantitative measures (tissue magnetic susceptibility, T1, T2*, fat fraction, adiabatic-T1ρ, magnetization transfer ratio, macromolecular fraction) with clinical MRI evaluation of hemosiderin, cartilage, and the OCJ, and we will correlate UTE and clinical MRI measures with histopathology, biochemistry, and biomechanics. In Aim 3 we will apply the optimized 3D UTE and clinical MRI techniques to evaluate outcome of prophylaxis in three groups of hemophilia patients with mild (n=20), moderate (n=20), and severe (n=20) HA at two time points (baseline and 12 months), and a group of age-matched healthy volunteers (n=20) once. Cross-sectional and longitudinal UTE and clinical MRI measures will be correlated with Hemophilia Joint Health Scores (HJHSs), Pettersson radiograph scores, and self-reported outcomes. We expect that UTE sequences will be more sensitive to early changes in hemophiliac joints than clinical MRI.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).